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Abstract:

The invention relates to pharmaceutical salts comprised of a
pharmaceutical active substance and of at least one sugar substitute, to
medicaments containing these salts, and to the use of these salts for
producing medicaments.

Claims:

1. A pharmaceutical salt of a salt-forming pharmaceutical active compound
and at least one salt-forming sugar substitute, wherein the salt-forming
pharmaceutical active compound is a salt-forming
1-phenyl-3-dimethylaminopropane compound selected from the group
consisting of: (a)
(-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol; (b)
(1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3--
diol; and (c) (-)-(1R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol.

2. The pharmaceutical salt according to claim 1, wherein the salt-forming
pharmaceutical active compound is
(-)-(1R,2R)-3-(3-Dimethylamino-l-ethyl-2-methyl-propyl)-phenol.

4. The pharmaceutical salt according to claim 1, wherein the salt-forming
pharmaceutical active compound is
(-)-(1R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol.

5. A pharmaceutical composition comprising a therapeutically effective
amount of the pharmaceutical salt according to claim 1 and optionally one
or more physiologically tolerable excipients.

6. A method of controlling pain comprising administering to a patient in
need thereof a pain-controlling effective amount of the pharmaceutical
salt of claim 1.

7. A method of controlling urinary incontinence comprising administering
to a patient in need thereof an urinary incontinence-controlling
effective amount of the pharmaceutical salt of claim 1.

Description:

[0001] The present invention relates to pharmaceutical salts of an active
compound and at least one sugar substitute, medicaments comprising these
salts, and the use of these salts for the production of medicaments.

[0002] On oral administration, a large number of pharmaceutical active
compounds having excellent activity lead to a strongly bitter, often
nauseating taste sensation in the patient. In some patients, lack of
adherence to the dosage instructions and a lack of acceptance of the
corresponding medicaments which release such an active compound as early
as during taking result from this negative taste experience.

[0003] The formulation of pharmaceutical active compounds having very good
water solubility to give medicaments frequently causes problems in
pharmaceutical practice. Thus the preparation of pharmaceutical forms
having controlled release is often made difficult on account of the very
good water solubility of active compound salts. A delaying of the release
of these active compounds can in fact be achieved, for example, by
coating the pharmaceutical forms with release-delaying film coatings.
This manner of delaying the release, however, is associated with a
relatively high outlay, since release-delaying film coatings from aqueous
coating systems are frequently only an inadequate diffusion barrier for
active compounds having very good water solubility. The preparation of
these delayed-release active compound preparations therefore requires
relatively complicated coating processes with multilayer films. If such
release-delaying coatings are applied from organic solvents, the
environmental and solvent residue problems associated therewith
additionally make the preparation of appropriate preparations more
expensive.

[0004] It was therefore the object of the present invention to make
available pharmaceutical combinations of active compounds which have no
bitter taste. Preferably, the corresponding active compounds should be
simpler to formulate and their release should be more effectively
delayed.

[0005] According to the invention, this object is achieved by the
provision of pharmaceutical salts, i.e.

[0006] physiologically tolerable salts, from a pharmaceutical active
compound and at least one sugar substitute.

[0007] The present invention therefore relates to pharmaceutical salts of
a pharmaceutical active compound and at least one sugar substitute, the
respective pharmaceutical salts of a sugar substitute and tramadol,
(+)-tramadol, (-)-tramadol, (+)-demethyltramadol and (-)-demethyltramadol
being excepted.

[0008] In a preferred embodiment of the present invention, the solubility
of the pharmaceutical salts according to the invention in water is
≦250 mg/ml of water, preferably ≦200 mg/ml, particularly
preferably ≦150 mg/ml, very particularly preferably ≦100
mg/ml. This can also be seen in particular in the fact that the water
solubility of the pharmaceutical salts according to the invention
compared with the water solubility of the best water-soluble salt of the
corresponding active compound according to Pharmazeutische Stoffliste
[Pharmaceutical Substance List], 12th edition ABDATA
Pharma-Daten-Service, 65735 Eschborn/Taunus, is preferably lowered by at
least 50%, preferably by at least 65%, particularly preferably by at
least 75%, very particularly preferably by at least 85%, compared with
the corresponding hydrochloride. The corresponding literature description
is hereby inserted as a reference and is thus regarded as part of the
disclosure.

[0009] According to the invention, suitable sugar substitutes are all
sugar substitutes which can form a salt with the respective
pharmaceutical active compound with formation of an at least singly
negatively charged form. According to the invention, pharmaceutical salts
are also included in which the pharmaceutical active compound has two or
more different sugar substitutes as salt components. Preferably, the
pharmaceutical salts according to the invention contain saccharin,
cyclamate or acesulfam, particularly preferably saccharin, as
salt-forming sugar substitutes.

[0010] According to the invention, suitable active compounds are all
pharmaceutical active compounds which can form a salt in anionic form
with the respective sugar substitute(s) with formation of an at least
singly positively charged form.

[0012] If the pharmaceutical active compound is a salt-forming analgesic,
it is preferably a salt-forming opioid or a salt-forming opioid analog,
such as disclosed in E. Friderichs, T. Christoph, H. Buschmann,
"Analgesics, and Antipyretics"; Ullmann's Encyclopedia of Industrial
Chemistry, Sixth Edition on CD-ROM, Wiley-VCH, Weinheim, 2000 or in
Pharmaceuticals, J. L. McGuire (Editor), Analgesics and Antipyretics,
Volume 2, pages 341-434, Wiley-VCH, Weinheim or ephedrine, chloroquine,
lidocaine, ethaverine, preglumetacin or triflupromazine. The
corresponding disclosures are hereby inserted as a reference and are thus
regarded as part of the present disclosure. Particularly preferably, the
salt-forming analgesic is selected from the group consisting of morphine,
codeine, ethylmorphine, diacetylmorphine, dihydrocodeine, etorphine,
hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone,
pethidine, ketobemidone, fentanyl, alfentanil, remifentanil, sufentanil,
levomethadone, levomethadyl, dextro-moramide, dextropropoxyphene,
diphenoxylate, piri-tramide, tilidine, buprenorphine, butorphanol,
dezozine, meptazinol, nalbuphine, nalorphine, pentazo-cine, flupirtin and
nefopam or a representative of the group consisting of ephedrine,
chloroquine, lidocaine, ethaverine, preglumetacin and triflupromazine.
Very particularly preferably, the salt-forming analgesic is a
salt-forming opioid or opioid analog selected from the group consisting
of morphine, codeine, hydrocodone, hydromorphone, oxycodone, tilidine,
fentanyl and buprenorphine.

[0013] Likewise preferably, the salt-forming active compound is a
salt-forming compound of 1-phenyl-3-dimethylamino-propane compounds of
the general formula I

##STR00001##

[0014] in which in each case

[0015] X is OH, F, Cl, H or an OCOR6 group,

[0016] R1 is a C1-4-alkyl group,

[0017] R2 is H or a C1-4-alkyl group and R3 is H or a
straight-chain C1-4-alkyl group or the radicals R2 and R3
together form a C4-7-cycloalkyl radical, and

[0018] if R5 is H, R4 is meta-O--Z where Z is H, C1-3-alkyl
PO(O--C1-4-alkyl)2, CO(OC1-5-alkyl),
CONH--C6H4--(C1-3-alkyl) CO--C6H4--R7,
where R7 is ortho-OCOC1-3-alkyl or meta- or
para-CH2N(R8)2 where R8 is C1-4-alkyl or
4-morpholino, or R4 is meta-S--C1-3-alkyl, meta-Cl, meta-F,
meta-CR9R10R11 where R9, R10 and R11 are H
or F, ortho-OH, ortho-O--C2-3-alkyl, para-F or
para-CR9R10R11 where R9, R10, R11 are H or
F, or if R5 is para-Cl, --F, --OH or --O--C1-3-alkyl, R4
is meta-Cl, --F, --OH or --O--C1-3-alkyl, or R4 and R5
together are 3,4-OCH═CH-- or 3,4--OCH═CHO--,

[0019] R6 is C1-3-alkyl,

[0020] in the form of their possible stereoisomers as racemates or
diastereomerically pure enantiomers or in the foam of mixtures of
enantiomers, in which the respective enantiomers are present in
nonequimolar amounts.

[0021] Preferred is a salt-forming compound of
1-phenyl-3-dimethylaminopropane compounds of the general formula I in
which X is OH, F, Cl or H, R1 is a C1-4-alkyl group, R2 is
H or CH3 and R3 is H or CH3 and if R5 is H, R4
is meta-O--C1-3-alkyl, meta-OH, meta-S--C1-3-alkyl, meta-F,
meta-Cl, meta-CH3, meta-CF2H, meta-CF3 or para-CF3 or
if R5 is a para-Cl or --F, R4 is meta-Cl or --F, or R4 and
R5 together are 3,4-OCH═CH--.

[0022] Particularly preferred is a salt-forming compound of
1-phenyl-3-dimethylaminopropane compounds of the general formula I in
which the radicals R2 and R3 have different meanings and which
are present in the form of their diastereomers having the configuration
Ia

[0032] The preparation of the salt-forming compounds of
1-phenyl-3-dimethylaminopropane compounds of the general formula I and,
if appropriate, the separation into the pure optical antipodes can be
carried out according to customary methods known to the person skilled in
the art. Preferably, the preparation and, if appropriate, the separation
is carried out as described in DE-A-4426245 or EP 0 693 475 B1, which are
hereby inserted as reference and are thus regarded as part of the
disclosure.

[0033] In a further preferred embodiment of the present invention, the
pharmaceutical salt according to the invention contains as a salt-forming
active compound a salt-forming compound of
6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general
formula II,

##STR00003##

[0034] in which in each case

[0035] R1' is H, OH, Cl or F, preferably H, OH or F,

[0036] R2' and R3' are identical or different and are H,
C1-4-alkyl, benzyl, CF3, OH,
OCH2--C6H5,O--C1-4-alkyl, Cl or F with the proviso
that at least one of the radicals R2' or R3' is H,

[0038] R5' is OC(O)C1-3-alkyl in the ortho-position or
CH2--N(R8')2 in the meta- or para-position, where R8'
is C1-4-alkyl or both radicals R8' together with N are the
4-morpholino radical, and

[0039] R6' and R7' are identical or different and are H or
C1-6-alkyl,

[0040] with the proviso that if both radicals R2' and R3' are H,
R4' is not CH3 if R1' is H, OH or Cl or R4' is not H
if R1' is OH,

[0041] in the form of their possible stereoisomers as racemates or
diastereomerically pure enantiomers or in the form of mixtures of
enantiomers, in which the respective enantiomers are present in
nonequimolar amounts.

[0042] Preferred are salt-foLming compounds of
6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general
formula II, which are present in the configuration as in the general
formula IIa,

##STR00004##

[0043] in which the phenyl ring and the dimethylaminomethyl group are in
each case arranged in an equatorial position to one another.

[0044] Particularly preferred is a salt-forming compound of
6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general
formula II selected from the group consisting of [0045]
(-)-(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol, [0046]
(1RS,3RS,6RS)-6-(dimethylaminomethyl)-1-(3-methoxy-phenyl)cyclohexane-1,3-
-diol and [0047]
(1RS,3RS,6RS)-6-(dimethylaminomethyl)-1-(3-hydroxy-phenyl)cyclohexane-1,3-
-diol.

[0048] The preparation of the salt-forming compounds of
6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general
formula II and, if appropriate, the separation into the optically pure
antipodes can be carried out according to customary methods known to the
person skilled in the art. Preferably, the preparation and, if
appropriate, the separation are carried out as described in
DE-A-19525137. The corresponding literature description is hereby
inserted as reference and is thus regarded as part of the disclosure.

[0049] In a further preferred embodiment of the present invention, the
pharmaceutical salt according to the invention contains as a salt-forming
active compound a salt-forming compound of
1-phenyl-2-dimethylamino-methylcyclohexan-1-ol compounds of the general
formula III,

[0056] in the form of their possible stereoisomers as racemates or
diastereomerically pure enantiomers or in the form of mixtures of
enantiomers, in which the respective enantiomers are present in
nonequimolar amounts.

[0057] Preferred are salt-forming compounds of
1-phenyl-2-dimethylaminomethylcyclohexan-1-ol compounds of the general
formula III, in which R1'' is H, C1-4-alkyl,
2'-methyl-2'-propenyl, cyclopentyl or fluoroethyl, with the proviso that
R1'' is C1-4-alkyl if A is S,

[0059] Particularly preferred are salt-forming compounds of
1-phenyl-2-dimethylaminomethylcyclohexan-1-ol compounds of the general
formula III, in which R1'' is H, methyl, ethyl, isopropyl,
2'-methyl-2'-propenyl, cyclopentyl or fluoroethyl, with the proviso that
R1'' is methyl if A is S,

[0061] Very particularly preferred are salt-forming compounds of
1-phenyl-2-dimethylaminomethylcyclohexan-1-ol compounds of the general
formula III which are present in the configuration of the formula IIIa,

##STR00008##

[0062] in which the phenyl ring and the dimethylaminomethyl group are in
each case arranged in an equatorial position to one another.

[0063] Most preferred is the salt-forming compound of
1-phenyl-2-dimethylaminomethylcyclohexan-1-ol compounds of the general
formula III selected from the group consisting of [0064]
(+)-(1R,2R,4S)-2-(dimethylaminomethyl)-4-(4-fluorobenzyloxy)-1-(3-methoxy-
phenyl)cyclohexanol, [0065]
(+)-(1R,2R,4S)-2-dimethylaminomethyl-4-(4-chlorobenzyloxy)-1-(3-methoxyph-
enyl)cyclohexanol and [0066]
(+)-(1R,2R,4S)-3-[2-dimethylaminomethyl-4-(4-fluorobenzyloxy)-1-hydroxycy-
clohexyl]phenol.

[0067] The preparation of the salt-forming compounds of
1-phenyl-2-dimethylaminomethylcyclohexan-1-ol compounds of the general
formula III and, if appropriate, the separation into the optically pure
antipodes can be carried out according to customary methods known to the
person skilled in the art. Preferably, the preparation and, if
appropriate, the separation are carried out as described in
DE-A-19547766, which is hereby inserted as reference and is thus regarded
as part of the disclosure.

[0068] In a further preferred embodiment of the present invention, the
pharmaceutical salt contains as a salt-forming active compound a
salt-forming compound of dimethyl-(3-arylbut-3-enyl)amine compounds of
the general formula IV, in which [sic]

##STR00009##

[0069] the radical R1''' is C1-5-alkyl and R2''' is H or
C1-5-alkyl or R1''' and R2''' together are
--(CH2)2-4--, --(CH2)2--CHR7''' or
--CH2--CHR7''' --CH2--,

[0081] R11''' is OC(O)--C1-3-alkyl in the ortho-position or
CH2--N--(R15''')2 in the meta- or para-position, where
R15''' is C1-4-alkyl or both radicals R15''' together with
N form the 4-morpholino radical,

[0082] R12''' and R13''' are identical or different and are H,
C1-6-alkyl or C3-8-cycloalkyl or R12''' and R13'''
together are --(CH2)3-8--,

[0083] R14''' is H, OH, C1-7-alkyl, O--C1-7-alkyl, phenyl,
O-aryl, CF3, Cl or F, with the proviso that the two radicals
R14''' are identical or different,

[0084] in the form of their possible stereoisomers as racemates or
diastereomerically pure enantiomers or in the foam of mixtures of
enantiomers, in which the respective enantiomers are present in
nonequimolar amounts.

[0085] Preferred are salt-forming compounds of
dimethyl-(3-arylbut-3-enyl)amine compounds of the general formula IV, in
which

[0092] with the proviso that two of the radicals R4''', R5''' or
R6''' are H, or

[0093] R4''' and R5''' together are --CH═C(R9''')--O--
or --CH═C(R9''')--S--, with the proviso that R6''' is H, or

[0094] R5''' and R6''' together are
--CH═CH--C(OR10''')═CH--, with the proviso that R4'''
is H, and

[0095] R7''' is C1-4-alkyl, CF3, Cl or F.

[0096] Particularly preferred are salt-forming compounds of
dimethyl-(3-arylbut-3-enyl)amine compounds of the general formula IV, in
which R1''' is CH3 or C3H7 and R2''' is H,
CH3 or CH2CH3, or R1''' and R2''' together are
--(CH2)2-3-- or --(CH2)2--CHR7''',

[0097] R3''' is H, CH3 or CH2CH3,

[0098] R4''' is H or OH, R5''' is H, OH, OCH3, CHF2 or
OR8''' and

[0099] R6''' is H, OH or CF3, with the proviso that two of the
radicals R4''', R5''' or R6''' are H, or

[0100] R4''' and R5''' together are --CH═C(CH3)--S--,
with the proviso that R6''' is H, or

[0101] R5''' and R6''' together are --CH═CH--C(OH)═CH--,
with the proviso that R4''' is H, and

[0102] R8''' is CO--C6H4--R11''' where R11''' is
OC(O)--C1-3-alkyl in the ortho-position.

[0103] Very particularly preferred are salt-forming compounds of
dimethyl-(3-arylbut-3-enyl)amine compounds of the general formula IV, in
which

[0104] R1''' is CH3 and R2''' is H or CH3 or
R1''' and R2''' together are --(CH2)2-3-- or
--(CH2)2--CH(CH3)--,

[0105] R3''' is H or CH3,

[0106] R4''' is H, R5''' is OH or OR8''', R6''' is H,
and R8''' is CO--C6H4--R11''' where R11''' is
OC(O)--CH3 in the ortho-position.

[0107] Most preferred is the salt-forming compound of
dimethyl-(3-arylbut-3-enyl)amine compounds of the general formula IV
trans-(-)-(1R)-3-[1-(2-dimethylamino-1-methylethyl)propenyl]phenol.

[0108] The preparation of the salt-forming compounds of
dimethyl-(3-arylbut-3-enyl)amine compounds of the general formula IV and,
if appropriate, the separation into the optically pure antipodes can be
carried out according to customary methods known to the person skilled in
the art. Preferably, the preparation and, if appropriate, the separation
of these compounds are carried out as described in EP 0 799 819 A1. The
corresponding literature description is hereby inserted as reference and
is thus regarded as part of the disclosure.

[0109] As salt-forming antiobesity agents, the pharmaceutical salt
according to the invention can preferably contain D-norpseudoephedrine,
phenylpropanolamine, amfepramone, mefenorex or ephedrine.

[0110] As salt-forming analeptics and/or antihypoxemics, the
pharmaceutical salt according to the invention can preferably contain
norfenefrine, heptaminol or amezinium, particularly preferably amezinium.

[0111] As salt-forming opioid antagonists, the pharmaceutical salt
according to the invention can preferably contain levallorphan, naloxone
or naltrexone.

[0112] As a salt-forming anthelmintic, the pharmaceutical salt according
to the invention can preferably contain pyrvinium.

[0153] The pharmaceutical salts according to the invention can be prepared
according to customary methods known to the person skilled in the art.
Preferably, for the preparation of the pharmaceutical salts according to
the invention, at least one salt of the respective active compound and at
least one salt of the respective sugar substitute are in each case
dissolved separately from one another in an amount of a solvent or
solvent mixture which is as small as possible, optionally with warming.

[0154] Both solutions are then combined, optionally mixed and optionally
cooled. If the pharmaceutical salt according to the invention of the
active compound and the sugar substitute precipitates at least partially
from the optionally cooled solution, this is separated off according to
customary methods, preferably by suction filtration. The pharmaceutical
salt separated off is then purified, if necessary, according to customary
methods known to the person skilled in the art, for example by
recrystallization, washing or by stirring in a suitable solvent.

[0155] If the pharmaceutical salt has still not completely precipitated,
the remaining solution is preferably concentrated completely on a rotary
evaporator and the pharmaceutical salt according to the invention is
extracted from the residue according to customary methods known to the
person skilled in the art and purified as described above.

[0156] The solvent or solvent mixture suitable in each case for the
preparation and the suitable reaction conditions, such as, for example,
temperature or reaction time, can be determined by the person skilled in
the art with the aid of simple preliminary tests. If both the active
compound salt and the salt of the sugar substitute have an adequate
solubility in water, the solvent used is preferably water. The salt of
the respective active compound employed is preferably its hydrochloride,
hydrobromide, phosphate, hydrogenphosphate, hydrogensulfate, sulfate,
nitrate or metilsulfate. The salt of the respective sugar substitute
employed is preferably its sodium, potassium, calcium or ammonium salt.

[0157] Of course, it is also possible to react the respective active
compound per se with [sic] the free acid of a sugar substitute with one
another in a suitable reaction medium and to isolate and, if appropriate,
to purify the pharmaceutical salt thus obtained according to customary
methods known to the person skilled in the art.

[0158] A further subject of the present invention are medicaments
comprising at least one pharmaceutical salt according to the invention
and, if appropriate, physiologically tolerable excipients. The
corresponding medicaments can be used for the treatment of the
indications known for the respective active compounds.

[0159] Preferably, medicaments according to the invention which contain at
least one pharmaceutical salt according to the invention of a
salt-forming opioid, opioid analog, ephedrine, chloroquine, lidocaine,
ethaverine, preglumetacin or triflupromaazine or a salt-forming compound
of the general formula I, II, III or IV indicated above and a sugar
substitute are employed for the control of pain. Preferably, the
medicaments according to the invention contain the corresponding
saccharinates as pharmaceutical salts of these active compounds.

[0160] For the treatment of urinary incontinence, medicaments according to
the invention are preferably employed which contain at least one
pharmaceutical salt of a salt-forming compound of the general formula I,
II, III or IV indicated above, or a compound from the group consisting of
oxybutymine, tolterodine, propiverine and trospium and a sugar
substitute. Preferably, the medicaments according to the invention
contain the corresponding saccharinates as pharmaceutical salts of these
active compounds.

[0161] The medicaments according to the invention can be present in solid,
semisolid or liquid form. Preferably, the medicaments according to the
invention are suitable for oral administration.

[0162] In a preferred embodiment, the medicament according to the
invention is present:--formulated as a gel, chewing gum, juice, spray,
tablet, chewable tablet, coated tablet, powder, if appropriate filled
into capsules, easily reconstitutable dry preparations, preferably as a
gel, as an aqueous or oily juice, as a sublingual spray, tablets or
chewable tablets.

[0163] Likewise preferably, the medicament according to the invention can
also be present formulated in multiparticulate form, preferably in the
form of microtablets, microcapsules, granules, active compound crystals
or pellets, particularly preferably in the form of microtablets, granules
or pellets, optionally filled into capsules or compressed to give
tablets.

[0164] If the medicament according to the invention is present in the form
of granules or pellets, these can preferably have a size in the range
from 0.1 to 3 mm, particularly preferably in the range from 0.5 to 2 mm.

[0165] If the medicament according to the invention is present in the form
of microtablets, these can preferably have a diameter in the range from
0.5 to 5 mm, particularly preferably in the range from 1 to 3 mm and very
particularly preferably in the range from 1 to 2 mm.

[0166] If the medicament according to the invention is present in the form
of active compound crystals, microparticles, micropellets or
microcapsules, these can preferably have a diameter in the range from 10
μm to 1 mm, particularly preferably in the range from 15 μm to 0.5
mm and very particularly preferably in the range from 30 μm to 200
μm.

[0167] Depending on embodiment, the medicaments according to the invention
can moreover contain the customary physiologically tolerable excipients
known to the person skilled in the art as further constituents.

[0168] If the medicaments according to the invention are present in the
form of tablets or microtablets, these can be present as physiologically
tolerable excipients, preferably microcrystalline cellulose, cellulose
ethers, lactose, starch, starch derivatives, sugar alcohols, calcium
hydrogenphosphate and the customary binders, flow regulators, lubricants
and/or disintegrants known to the person skilled in the art.

[0169] If the medicaments according to the invention are present in the
form of gels or chewing gums, these can preferably contain methylparaben,
propylparaben, xylitol and/or xanthan gum as physiologically tolerable
excipients.

[0170] If the medicaments according to the invention are present in the
form of pellets, granules or micropellets, these can preferably contain
microcrystalline cellulose, cellulose ethers, lactose, starch and starch
derivatives, sugar alcohols, calcium hydrogenphosphate, fatty alcohols,
esters of glycerol or fatty acid esters as physiologically tolerable
excipients.

[0171] If the medicaments according to the invention are present in the
form of microcapsules or microparticles, these can contain, depending on
the nature of the process employed for their preparation, the customary
physiologically tolerable excipients known to the person skilled in the
art.

[0172] The medicaments according to the invention can be prepared by
customary methods known to the person skilled in the art.

[0173] If the medicaments according to the invention are present in the
form of tablets, preferably the pharmaceutical salt according to the
invention and, if appropriate, the physiologically tolerable excipients
are preferably mixed homogeneously with one another, processed to give
granules by means of moist, dry or melt granulation and compressed to
give tablets or produced by direct tableting of the pharmaceutical salt
with further excipients. In addition, the tablets can preferably be
produced by compression of optionally coated pellets, active compound
crystals, microparticles or microcapsules.

[0174] The medicaments according to the invention in the form of pellets
can preferably be produced by mixing the pharmaceutical salt and
physiologically tolerable excipients, extrusion and spheronization, by
build-up pelletization or by direct pelletization in a high-speed mixer
or in the rotor fluidized bed. The pellets are particularly preferably
prepared by extrusion of moist masses and subsequent spheronization.

[0175] Microcapsules are prepared according to customary
microencapsulation processes, such as, for example, by spray drying,
spray solidification or coacervation.

[0176] The medicaments according to the invention in semisolid form, such
as, for example, gels or chewing guns, are preferably suitable for the
administration of the pharmaceutical salt according to the invention via
the oral mucosa, the medicaments according to the invention in solid or
liquid form, such as, for example, oily or aqueous juices, tablets or
multiparticulate forms are preferably suitable for the administration of
the pharmaceutical salt according to the invention via the gastric tract.
If the absorption of active compound from the medicament according to the
invention in solid form is only intended via the gastric tract, they must
have at least one enteric coating. This enteric coating enables them to
pass through the gastric tract undissolved and the pharmaceutical salt is
only released in the intestinal tract. Preferably, the enteric coating
dissolves at a pH of between 5 and 7.5.

[0177] The medicament according to the invention can contain the
pharmaceutical salt according to the invention also partially or
completely in delayed-release form.

[0178] The delaying of the release of active compound is preferably based
on the application of a release-delaying coating, on embedding in a
release-delaying matrix, binding to an ion-exchange resin or on a
combination of these abovementioned release-delaying methods.

[0179] Preferably, the release-delaying coating is based on a
water-insoluble, optionally modified natural or synthetic polymer or on a
natural, semisynthetic or synthetic wax or fat or fatty alcohol or a
mixture of at least two of these abovementioned components.

[0180] Water-insoluble polymers employed for the preparation of a
release-delaying coating are preferably poly(meth) acrylates,
particularly preferably poly(C1-4) alkyl (meth)acrylates,
poly(C1-4)dialkylamino-(C1-4)-alkyl (meth)acrylates and/or
their copolymers, very particularly preferably ethyl acrylate/methyl
methacrylate copolymers having a molar ratio of the monomers of 2:1,
ethyl acrylate/methyl methacrylate/trimethylammonium ethyl methacrylate
chloride copolymers having a molar ratio of the monomers of 1:2:0.1,
ethyl acrylate/methyl methacrylate/trimethylammonium ethyl methacrylate
chloride copolymers having a molar ratio of the monomers of 1:2:0.2 or a
mixture of at least two of these abovementioned polymers as a coating
material.

[0181] These coating materials are obtainable on the market as 30%
strength by weight aqueous latex dispersions under the names Eudragit
RS30D®, Eudragit NE30D® and Eudragit RL30D® and are
preferably also employed as a coating material as such.

[0182] Likewise preferably, the water-insoluble polymers employed for the
preparation of the release-delaying coating for the medicaments according
to the invention can be polyvinyl acetates, optionally in combination
with further excipients. These are obtainable on the market as an aqueous
dispersion containing 27% by weight of polyvinyl acetate, 2.5% by weight
of povidone and 0.3% by weight of sodium lauryl sulphate (Kollicoat SR 30
D®).

[0183] In a further preferred embodiment, the release-delaying coatings of
the medicaments according to the invention are based on water-insoluble
cellulose derivatives, preferably alkylcelluloses, such as, for example,
ethylcellulose, or on cellulose esters, such as, for example, cellulose
acetate, as a coating material. The coatings of ethylcellulose or
cellulose acetate are preferably applied from aqueous pseudolatex
dispersion. Aqueous ethylcellulose-pseudolatex dispersions are stocked on
the market as 30% strength by weight dispersions (Aquacoat®) or as
25% strength by weight dispersions (Surelease®) and as such are
preferably also employed as a coating material.

[0184] As natural, semisynthetic or synthetic waxes, fats or fatty
alcohols, the release-delaying coating in the medicament according to the
invention can preferably contain carnauba wax, beeswax, glycerol
monostearate, glycerol monobehenate (Compritol ATO888®), glycerol
ditripalmitostearate (Precirol AT05®), microcrystalline wax, cetyl
alcohol, cetylstearyl alcohol, or a mixture of at least two of these
components.

[0185] If the release-delaying coating is based on a water-insoluble,
optionally modified natural and/or synthetic polymer, the coating
dispersion or solution can contain, in addition to the corresponding
polymer, a customary physiologically tolerable plasticizer known to the
person skilled in the art in order to lower the minimum film temperature
necessary.

[0186] Suitable plasticizers are, for example, lipophilic diesters of an
aliphatic or aromatic dicarboxylic acid of C6-C40 and an
aliphatic alcohol of C1-C8, such as, for example, dibutyl
phthalate, diethyl phthalate, dibutyl sebacate or diethyl sebacate,
hydrophilic or lipophilic esters of citric acid, such as, for example,
triethyl citrate, tributyl citrate, acetyltributyl citrate or
acetyltriethyl citrate, polyalkylene glycols, such as, for example,
polyethylene glycols or propylene glycols, esters of glycerol, such as,
for example, triacetin, Myvacet® (acetylated mono- and diglycerides,
C23H44O5 to C25H47O7), medium-chain
triglycerides (Miglyol®), oleic acid or mixtures of at least two of
the abovementioned plasticizers.

[0188] Preferably, the release-delaying coating contains the
plasticizer(s) in amounts of 5 to 50% by weight, particularly preferably
10 to 40% by weight and very particularly preferably 10 to 30% by weight,
based on the amount of the polymer employed.

[0189] In individual cases, for example for cellulose acetate, higher
amounts of plasticizers, preferably up to 110% by weight, based on the
amount of cellulose acetate, can also be employed.

[0190] In addition, the release-delaying coating can contain further
customary excipients known to the person skilled in the art, such as, for
example, lubricants, preferably talc or glycerol monostearate, color
pigments, preferably iron oxides or titanium dioxide, or surfactants,
such as, for example, Tween 80®.

[0191] The release profile of the delayed active compound component can be
adjusted by the customary methods known to the person skilled in the art,
such as, for example, by the thickness of the coating or by the use of
further excipients as constituents of the coating. Suitable excipients
are, for example, hydrophilic or pH-dependent pore-forming agents, such
as, for example, sodium carboxymethylcellulose, cellulose acetate
phthalate, hydroxypropylmethylcellulose acetate succinate, lactose,
polyethylene glycol or mannitol or water-soluble polymers, such as, for
example, polyvinylpyrrolidone or water-soluble celluloses, preferably
hydroxypropylmethylcellulose or hydroxypropylcellulose.

[0192] The release-delaying coating can also contain insoluble or
lipophilic excipients, such as, for example, alkylized silicone, which is
stocked on the market, for example, as Aerosil R972®, or magnesium
stearate for the further intensification of the delaying.

[0193] The respective formulation of the medicament according to the
invention can optionally also contain, in addition to the
release-delaying coating, at least one further coating. This can be, for
example, a coating for improving the taste or an enteric coating.

[0194] The enteric coating is preferably based on methacrylic acid/methyl
methacrylate copolymers having a molar ratio of the respective monomers
of 1:1 (Eudragit L®), methacrylic acid/methyl methacrylate copolymers
having a molar ratio of the respective monomers of 1:2 (Eudragit S®),
methacrylic acid/ethyl acrylate copolymers having a molar ratio of the
respective monomers of 1:1 (Eudragit L30D-55®), methacrylic
acid/methyl acrylate/methyl methacrylate copolymers having a molar ratio
of the respective monomers of 7:3:1 (Eudragit FS®), shellac
hydroxypropylmethylcellulose acetate succinate, cellulose acetate
phthalate or a mixture of at least two of these abovementioned
components, which can optionally also be employed in combination with the
abovementioned water-insoluble poly(meth)acrylates, preferably in
combination with Eudragit NE30D® and/or Eudragit RL® and/or
Eudragit RS®.

[0195] The coatings can be applied by customary processes suitable for the
respective coating and known to the person skilled in the art, such as,
for example, by spraying on solutions, dispersions or suspensions, by
melt processes or by powder application processes. The solutions,
dispersions or suspensions can be employed in the form of aqueous and/or
organic solutions or dispersions. In this context, aqueous dispersions
are preferably employed. Organic solvents which can preferably be used
are alcohols, for example ethanol or isopropanol, ketones, such as, for
example, acetone, esters, for example ethyl acetate, chlorinated
hydrocarbons, such as, for example, dichloromethane, with alcohols or
ketones being particularly preferably employed. It is also possible to
employ mixtures of at least two of the abovementioned solvents.

[0196] If the medicament is present in multiparticulate form and the
active compound is to be released at least partially in delayed form, the
release-delaying coating is preferably applied such that the
multiparticulate forms comprising the active compound salt are coated
after their preparation with the corresponding polymers and, if
appropriate, another active compound and/or the same active compound salt
and, if appropriate, further physiologically tolerable excipients from
aqueous and/or organic media, preferably from aqueous media, with the aid
of the fluidized bed process and the coating is preferably simultaneously
dried in the fluidized bed at customary temperatures and, if appropriate,
annealed if necessary.

[0197] Preferably, the drying of the coating is carried out for
poly(meth)acrylate coatings at a feed air temperature in the range from
30 to 50°, particularly preferably in the range from 35 to
45° C.

[0198] For coatings based on cellulose, such as, for example,
ethylcellulose or cellulose acetate, the drying is preferably carried out
at a temperature in the range from 50 to 80° C., particularly
preferably in the range from 55 to 65° C.

[0199] Wax coatings can be applied by melt coating in the fluidized bed
and cooled at temperatures below the respective melt range after the
coating for complete solidification. The application of wax coatings can
also be carried out by spraying on their solutions in organic solvents.

[0200] For the modification of the active compound release profile, the
medicament according to the invention can contain the pharmaceutical salt
whose release is to be delayed also in a release-delaying matrix,
preferably uniformly dispersed.

[0201] Matrix materials which can be used are physiologically tolerable,
hydrophilic materials which are known to the person skilled in the art.
Preferably, the hydrophilic matrix materials used are polymers,
particularly preferably cellulose ethers, cellulose esters and/or acrylic
resins. Very particularly preferably, the matrix materials employed are
ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,
hydroxymethylcellulose, poly(meth)acrylic acid and/or their derivatives,
such as, for example, their salts, amides or esters.

[0202] Likewise preferred are matrix materials made of hydrophobic
materials, such as hydrophobic polymers, waxes, fats, long-chain fatty
acids, fatty alcohols or appropriate esters or ethers or mixtures of at
least two of the abovementioned materials. Particularly preferably, the
hydrophobic materials employed are mono- or diglycerides of
C12-C30-fatty acids and/or C12-C30-fatty alcohols
and/or waxes or mixtures of at least two of the abovementioned materials.

[0203] It is also possible to employ mixtures of the above-mentioned
hydrophilic and hydrophobic materials as a release-delaying matrix
material.

[0204] The release-delaying matrix can be prepared by the customary
methods known to the person skilled in the art.

[0205] A further subject of the invention is also the use of at least one
pharmaceutical salt according to the invention and, if appropriate,
physiologically tolerable excipients for the production of a medicament.
The corresponding medicaments can be used for the treatment of the
indications known for the respective active compounds.

[0206] Preferred is the use of at least one pharmaceutical salt of a
salt-forming opioid, opioid analog, ephedrine, chloroquine, lidocaine,
ethaverine, preglumetacin, truflupromazine or a salt-forming compound of
the general formula I, II, III or IV indicated above for the production
of a medicament for the control of pain, the salts of these active
compounds used preferably being their saccharinates.

[0207] Likewise preferred is the use of at least one pharmaceutical salt
of a salt-forming compound of the general formula I, II, III or IV
indicated above for the production of a medicament for the treatment of
urinary incontinence, the salts of these active compounds used preferably
being their saccharinates.

[0208] The total amount of the respective pharmaceutical salt to be
administered to the patient varies, for example, depending on the the
weight of the patient, on the indication and the degree of severity of
the pain or of the disorder. It is known to the person skilled in the art
on account of the properties of the respective active compounds in what
doses these are to be administered in order to achieve the desired
effect.

[0209] The pharmaceutical salts according to the invention of a
pharmaceutical active compound and a sugar substitute are distinguished
compared with the conventionally used salts of these active compounds
customarily by a lower solubility in water. Preferably, these are the
saccharinates of the respective active compounds, whose water solubility
is usually ≦250 mg/ml and, compared with the water solubility of
the conventional salts of the corresponding active compound, is usually
lowered by at least 50%.

[0210] By this means, the formulation of these pharmaceutical salts to
give medicaments, for example the preparation of granules by extrusion,
is also simplified. On account of the altered solubility, the
pharmaceutical salts according to the invention further enable more
effective release-delaying of the active compound using customary
delaying processes in comparison to salts customarily used.
Delayed-release medicaments which contain these pharmaceutical salts
according to the invention can therefore be produced more simply and more
inexpensively. This also applies for other modifications of the
medicaments according to the invention, such as, for example, with
enteric coatings.

[0211] From the medicaments according to the invention, which are employed
for the administration of the respective pharmaceutical salt via the oral
mucosa or the gastric tract, a largely controlled release of the
respective active compound without the use of a release-delaying matrix
and/or a release-delaying coating, but if appropriate with an enteric
coating, is moreover achieved.

[0212] The medicaments according to the invention in the form to be
administered orally, which release the respective active compound as
early as on or immediately after administration, furthermore have the
advantage that their strongly bitter or nauseating taste is compensated
by the simultaneous release of the sugar substitute. The adherence to the
dosage instructions in the patients thereby improves and the medicaments
which contain the respective active compound as a salt experience a
greater acceptance. The medicaments according to the invention are
moreover also suitable for diabetics.

[0213] For a large number of the abovementioned active compounds, the
water solubility of the conventional active compound salts is known, for
example from Pharmazeutische Stoffliste [Pharmaceutical Substance List],
12th edition ABDATA Pharma-Daten-Service, 65735 Eschborn/Taunus. The
corresponding disclosure [sic] is hereby inserted as reference and is
thus regarded as part of the disclosure.

[0214] If the water solubility of an active compound salt is not known, it
can be determined according to the method indicated below, according to
which the water solubility of the pharmaceutical salts according to the
invention has also been determined:

[0215] In a clear colorless vessel made of transparent material, such as,
for example, glass or plastic, 1 ml of ion-free water or a fraction
(amount A in ml) thereof is introduced at a temperature of 20° C.
While stirring with a magnetic stirrer rod, the conventional active
compound salt to:be tested or the pharmaceutical salt according to the
invention was then added in portions.

[0216] If the amount of salt B added (in mg) completely dissolved, further
amounts of the respective salt were slowly added. Each further addition
was recorded and the solution behavior observed. As soon as the first
turbidity due to undissolved salt was found by observation against a
suitable background, stirring was continued for a further 10 minutes. If
undissolved constituents subsequently remained, the sum C (in mg) of the
amount of substance employed was determined. If a clear solution resulted
again on stirring, further small amounts of the respective salt were
added and the mixture was in each case stirred again for 10 minutes until
a first turbidity remained on account of undissolved salts. The excess
amount of undissolved substance was then brought into solution with
stirring by addition of small amounts of water. After a clear solution
had been obtained, the sum D (in ml) of the amount of water employed was
determined. The solubility of the respective salt per 1 ml of water was
then calculated according to the following formula:

[0217] If the amount B added (in mg) of the respective salt did not
dissolve immediately and a turbidity resulted, after the addition of the
salt the mixture was stirred for a further 10 minutes. If undissolved
salt still remained then, the undissolved portion was brought into
solution by addition of small amounts of water with stirring. After
obtainment of a clear solution, the sum E (in ml) of the amounts of water
employed was determined. The solubility of the respective salt per 1 ml
of water was then calculated according to the following formula:

Water solubility of the active
compound salt in mg / ml of
water = B E ##EQU00002##

[0218] The invention is explained below with the aid of examples. These
explanations are only by way of example and do not restrict the general
inventive concept.

EXAMPLES

Example 1

[0219] The preparation and the subsequent separation of the optically pure
compound (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol was
carried out according to DE-A-4426245. The corresponding part of the
disclosure [sic] is hereby inserted as reference and is thus regarded as
part of the disclosure.

[0220] For the preparation of
(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol
saccharinate, 2.58 g (10 mmol) of
(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol
hydrochloride and 2.42 g (10 mmol) of saccharin-sodium dihydrate were in
each case completely dissolved with warming in an amount of water which
was as small as possible. Both solutions were then mixed with one another
with stirring and then placed in a cool place overnight. The precipitated
(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol
saccharinate was separated off from the supernatant mother liquor,
purified with ethanol and isolated according to conventional methods.

Example 2

[0221] For the preparation of diphenhydramine saccharinate, 5.0 g (17.1
mmol) of diphenhydramine hydrochloride and 4.13 g (17.1 mmol) of
saccharin-sodium dihydrate were in each case completely dissolved with
warming in an amount of water which was as small as possible. Both
solutions were then mixed with one another with stirring and then placed
in a cool place overnight. The precipitated diphenhydramine saccharinate
was separated off from the supernatant mother liquor, purified with
ethanol and isolated according to conventional methods.

Example 3

[0222] For the preparation of verapamil saccharinate, 415 mg (0.845 mmol)
of verapamil hydrochloride and 204 mg (0.845 mmol) of saccharin-sodium
dihydrate were in each case completely dissolved with warming in an
amount of water which was as small as possible. Both solutions were then
mixed with one another with stirring and then placed in a cool place
overnight. The precipitated verapamil saccharinate was separated off from
the supernatant mother liquor, purified with ethanol and isolated
according to conventional methods.

Example 4

[0223] For the preparation of morphine saccharinate, 285 mg (0.76 mmol) of
morphine hydrochloride trihydrate and 183 mg (0.76 mmol) of
saccharin-sodium dihydrate were in each case completely dissolved with
warming in an amount of water which was as small as possible. Both
solutions were then mixed with one another with stirring and then placed
in a cool place overnight. The precipitated morphine saccharinate was
separated off from the supernatant mother liquor, purified with ethanol
and isolated according to conventional methods.

Example 5

[0224] For the preparation of an oral gel, 0.33 g of methylparaben, 0.05 g
of propylparaben and 75.0 g of xylitol were first dissolved in 198.0 g of
purified water at a temperature of 80° C. and the mixture was then
cooled to 40° C. Then, initially 0.94 g of diphenhydramine
saccharinate obtained according to example 2 and subsequently 2 g of
xanthan gum were added with stirring, stirring was continued for one hour
and evaporated water was replaced. After cooling to a temperature of 20
to 25° C., the mixture was flavored with 0.625 g of Tutti-Frutti
9/008897 (Dragoco Gerberding & Co. AG, 37603 Holzminden) while stirring.

Example 6

[0225] 5 g of comminuted chewing gum mass (Popeye Amural Confections,
Yorkville, Ill., USA) were warmed to a temperature of 30 to 40° C.
in a Fanta dish. 187.9 mg of diphenhydramine saccharinate obtained
according to example 2 were then incorporated into the viscous chewing
gum mass using a pestle. The homogeneous mass was then portioned into
teflonized molds to give portions of 1 g each.

[0226] The taste test showed that the chewing gums which contained the
diphenhydramine saccharinate had an excellent taste at the start and were
still enjoyable even after a relatively long chewing time.

Example 7

[0227] For the preparation of a juice on an aqueous basis, 0.33 g of
methylparaben, 0.05 g of propylparaben and 75.0 g of xylitol were
dissolved in 199.22 g of purified water at a temperature of 80° C.
The mixture was cooled to 40° C. and 78.5 mg of
(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol saccharinate
obtained according to example 1 were added with stirring. 0.25 g of
xanthan gum was then added, stirring was continued for one hour and
evaporated water was replaced. After cooling to [lacuna] temperature of
20 to 25° C., the mixture was flavored while stirring with 0.075 g
of orange-mandarin flavor 10888-56 (Givaudan Roure Flavors Ltd. CH 8600
Dubendorf).

Example 8

[0228] In this example, the water solubility of certain pharmaceutical
salts and of conventional salts of the corresponding active compound was
determined according to the method indicated above. The solubility values
thus obtained are presented in table 1 below:

[0229] As can be seen from the solubility values according to table 1, the
solubility of the respective active compound saccharinates is lowered
compared with the corresponding conventional active compound salts.

Patent applications by Heinrich Kugelmann, Aachen DE

Patent applications by Johannes BartholomÄus, Aachen DE

Patent applications by GRÜNENTHAL GMBH

Patent applications in class The chain consists of two or more carbons which are unsubtituted or have acyclic hydrocarbyl substituents only

Patent applications in all subclasses The chain consists of two or more carbons which are unsubtituted or have acyclic hydrocarbyl substituents only